EP0478062B1 - Préparation in-situ de diisopinocampheyl chloroborane - Google Patents

Préparation in-situ de diisopinocampheyl chloroborane Download PDF

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Publication number
EP0478062B1
EP0478062B1 EP91202396A EP91202396A EP0478062B1 EP 0478062 B1 EP0478062 B1 EP 0478062B1 EP 91202396 A EP91202396 A EP 91202396A EP 91202396 A EP91202396 A EP 91202396A EP 0478062 B1 EP0478062 B1 EP 0478062B1
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reaction
compound
formula
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alkoxy
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EP0478062A1 (fr
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Pamela M. Simpson
David M. Tschaen
Thomas R. Verhoeven
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Merck and Co Inc
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Merck and Co Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/32—Oxygen atoms
    • C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/027—Organoboranes and organoborohydrides

Definitions

  • the invention concerns the preparation of diisopinocampheylborane.
  • the invention also relates to the use of a crude diisopinocampheyl borane product in the reduction of prochiral ketones.
  • diisopinocampheylborane was prepared and isolated by crystallization prior to its conversion to the active reducing agent diisopinocampheylchloroborane. This intermediate is highly sensitive to both oxygen and water, thus complicating its isolation.
  • Diisopinocampheylborane is prepared in-situ, without isolation or discrete purification, and yet surprisingly performs in an equal manner to isolated reagent. This represents a major process advantage since both the diisopinocampheylborane and the diisopinocampheylchloroborane are highly reactive reagents, sensitive to both oxygen and water. Thus handling of these reagents, which would be necessitated during isolation, presents difficulty.
  • the present invention also concerns the use of a crude diisopinocampheylborane product in the preparation of the chiral alcohols such as those of the intermediate compounds of Formula B.
  • Co-pending European patent application no. 91305816.0 discloses a process of making intermediate butyrolactone of Formula D. That process is outlined in Scheme 1.
  • Step A an in situ prepared acyl anion equivalent, Compound E , which is derived from a substituted benzaldehyde is chemoselectively added to an ⁇ , ⁇ -unsaturated ester, to yield Compound A .
  • This single transformation assembles the requisite carbon framework from commercially available precursors.
  • Step B an enantioselective reduction utilizes ⁇ -chlorodiisopinocampheyl borane in an unprecedented manner to produce an optically enriched 4-aryl-4-hydroxy-butanoate, Compound B .
  • Steps C to D conversion of Compound B to the title lactone Compound D is accomplished via a novel, internally assisted saponification followed by a mild acid catalyzed lactonization. Both saponification and lactonization are effected without racemization. Thereafter, controlled crystallization of Compound D efficiently enriches the optical purity to greater than 99.5%.
  • the present invention is directed to in-situ preparation of diisopinocampheyl chloro borane, and the use of same in the reduction of prochiral ketones to alcohols such as the optically active alcohols of Formula B.
  • the instant invention encompasses a process of making diisopinocampheylchloroborane comprising:
  • reaction product e.g. compound of Formula 1 or 2
  • solvent unreacted reagents, or possible side reaction products, that may be present in the reaction vessel.
  • (1R)-(+)- ⁇ -pinene shall be understood to have a purity of about 91% ee to 95% ee.
  • the etheral solvents include, but are not limited to ethers such as diethyl ether di- n -butyl and diisopentyl ethers, anisole, cyclic ethers such as tetrahydropyran, 4-methyl-1,3-dioxane, dihydropyran, tetrahydrofurfuryl methyl ether, ethyl ether, furan and 2-ethoxytetrahydrofuran, most preferably tetrahydrofuran.
  • ethers such as diethyl ether di- n -butyl and diisopentyl ethers
  • anisole cyclic ethers
  • cyclic ethers such as tetrahydropyran, 4-methyl-1,3-dioxane, dihydropyran, tetrahydrofurfuryl methyl ether, ethyl ether, furan and 2-ethoxytetrahydrofuran, most preferably
  • the reaction step (a) can be conducted at -25 to 25°C, preferably at 0 to 5°C.
  • the reaction is allowed to proceed until essentially complete in about 1 to 100 hours, preferably 18 hours. While step (a) may be carried out at up to 100 atmospheres, the reaction is preferably carried out at ambient pressure.
  • the pinene is added to the borane in THF in the absence of oxygen and in a manner calculated to maintain the temperature of the reaction mixture in a range of 0 to 5°C.
  • the molar ratio of pinene to Borane methyl sulfide should be approximately 2:1. Preferable there should be an excess of pinene, such as 2.1 to 3:1.
  • acid chloride may include, but is not limited to hydrochloric acid.
  • the acid chloride is preferably added in a etheral solvent as described above; preferably the etheral solvent selected for step (a).
  • the molar amount of acid chloride added should be approximately equal to that of the borane added in step (a).
  • the reaction step (b) can also be conducted at -25 to 25°C, preferably at 0 to 5°C.
  • the reaction is allowed to proceed until essentially complete in about 0.1 to 1 hours, preferably 15 to 30 minutes. While step (b) may be carried out at up to 100 atmospheres, the reaction is preferably carried out at ambient pressure.
  • the instant invention also encompasses a process for reducing a prochiral ketone to produce an optically active alcohol of high optical purity comprising: Reacting a prochiral ketone with a reducing agent which is, without further purification the product of step (b) for from 7 hours to 24 days at a temperature from -25°C to ambient temperature at ambient pressure until the reaction is complete.
  • This embodiment represents an improvement over U.S. 4,866,181 issued to Brown on September 12, 1989.
  • this embodiment is useful for carrying out reductions of the following reaction types:
  • this latter embodiment encompasses a process for the preparation of 5-aryl- ⁇ -butyrolactones. These compounds are critical intermediates for the synthesis of optically pure trans -2,5-diaryl tetrahydrofurans which are potent antagonists of Platelet Activating Factor.
  • the invention concerns a process of making Compounds of Formula B wherein
  • contacting Step A is carried out in two stages.
  • the first stage comprises degassing a solution of Compound F in the first solvent, followed by addition of a catalytic amount of alkali metal cyanide to the solution of Compound F in the first solvent.
  • Degassing may conveniently be accomplished by bubbling nitrogen gas through the solution for 10 minutes under ambient conditions.
  • the cyanide is then added and the reagents are stirred for about 10 to 100 minutes. 30 minutes under constant stirring has proven quite satisfactory.
  • While the first stage may be carried out at up to 100 atmospheres, this stage is preferably carried out at ambient pressure. Temperature can range from 20 to 30°C, but is preferably at about 25°C.
  • the ratio of alkali metal cyanide to compound F is 0.1 to 0.3 moles per 100 moles, most preferably 0.25 mole.
  • Contacting Step A is then completed by direct addition of the acrylate derivative, preferably over a 50 to 60 minute period, at from 0 to 25°C.
  • the first solvent includes, but is not limited to, such solvents as mono or di C 1-6 alkyl amide derivatives such as dimethylformamide (DMF); di-C 1-6 alkyl sulfoxide, such as methylsulfoxide or aqueous C1-6 alcohol, such as ethanol, most preferably DMF.
  • the alkali metal cyanide is a cyanide such as sodium, potassium or lithium cyanide, preferably sodium cyanide.
  • the acrylate derivative is preferably a sterically hindered acrylate, such as CO 2 -t-C 4 C 9 .
  • Critical to reaction success was the discovery that oxygen exclusion is a requirement. In its presence, oxidative decomposition leading to by-products which depress the yield significantly;
  • etheral solvents include, but are not limited to ethers such as diethyl ether di- n -butyl and diisopentyl ethers, anisole, cyclic ethers such as tetrahydropyran, 4-methyl-1,3-dioxane, dihydropyran, tetrahydrofurfuryl methyl ether, ethyl ether, furan and 2-ethoxytetrahydrofuran, most preferably tetrahydrofuran.
  • ethers such as diethyl ether di- n -butyl and diisopentyl ethers
  • anisole cyclic ethers
  • cyclic ethers such as tetrahydropyran, 4-methyl-1,3-dioxane, dihydropyran, tetrahydrofurfuryl methyl ether, ethyl ether, furan and 2-ethoxytetrahydrofuran, most preferably
  • the reaction can be conducted at -25 to 25°C preferably at 0 to 5°C.
  • the reaction is allowed to proceed until essentially complete in about 1 to 100 hours, preferably 18 hours. While the pretreatment may be carried out at up to 100 atmospheres, the reaction is preferably carried out at ambient pressure.
  • the ⁇ -hydroxy butanoate derivative Compound B is provided in typically 80-90% yields with an enantiomeric excess (ee) of 92%.
  • Use of the (-)-chloroborane enantiomer provides the 4S-alcohol while the (+)-chloroborane enantiomer yields the 4R-alcohol. Thus both enantiomers of B are accessible by this invention.
  • Step B comprises:
  • tetrahydrofuran is once again the etheral solvent of choice.
  • the reacton can be carried out at -25 to 25°C.
  • the pinene is added to the borane in THF in the absence of oxygen and in a manner calculated to maintain the temperature of the reaction mixture in a range of 0 to 5°C. This portion of the reaction is allowed to proceed until essentially complete in about 1 to 100 hours, preferably 18 hours.
  • acid chloride includes but is not limited to hydrochloric acid.
  • the compound of formula A is added at from 0 to 5°C. This portion of the reaction is allowed to proceed until for about 1 to 100 hours, preferably 74 hours, after which water, alkanol and neutralizing agent are added, preferably at under 15°C. This portion of the reaction is allowed to proceed until essentially complete in 1 to 100 hours, typically at ambient temperature for 2 hours.
  • the ratio of borane to pinene and acid chloride in pinene is approximately 1:2 with preferably an excess of pinene.
  • the ratio of pinene to the butyrate (Formula A) is approximately 1:3.5; preferably with an excess of pinene.
  • alcohol includes, but is not limited to C 1-6 alkanol, preferably ethanol.
  • sodium hydroxide is the preferred alkali metal hydroxide.
  • etheral solvents include, but are not limited to ethers such as diethyl ether di- n -butyl and diisopentyl ethers, anisole, cyclic ethers such as tetrahydropyran, 4-methyl-1,3-dioxane, dihydropyran, tetrahydrofurfuryl methyl ether, ethyl ether, furan and 2-ethoxytetrahydrofuran, most preferably tetrahydrofuran.
  • the molar ratio of alkali metal hydroxide to Compound C should be at least 1 to 1, preferably 1.5 to 1 or greater.
  • the time, temperature and pressure of the reaction are not considered critical.
  • the reaction can be conducted at -25 to 50°C , preferably at 25°C.
  • the reaction is allowed to proceed until essentially complete in about 20 to 200 minutes, preferably 75 minutes. While the pretreatment may be carried out at up to 100 atmospheres, the pretreatment is preferably carried out at ambient pressure.
  • Step 2 is the intramolecular assistance provided by the ⁇ -hydroxyl moiety in compound B which facilitates removal of the R-oxy group under basic conditions. Normally recommended acid catalyzed procedures for hydrolysis of the R ester would likely result in significant racemization of this substrate. Saponification yields compound C as a free acid salt, readily extractable into water and consequently easily separated from the neutral pinanyl by-products resulting from the chiral reduction step.
  • the second solvent includes, but is not limited to, an etheral solvent, as defined above, or a C 6-10 linear, branched or cyclic hydrocarbon solvent.
  • Toluene is preferred.
  • the time, temperature and pressure of the reaction are not considered critical.
  • the reaction can be conducted at 50 to 80°C , preferably at 70°C.
  • the reaction is allowed to proceed until essentially complete in about 20 to 200 minutes, preferably 90 minutes. While the reaction may be carried out at up to 10-100 atmospheres, the reaction is preferably carried out under ambient pressure in a nitrogen atmosphere.
  • racemization does not occur, even with highly electron rich substrates .
  • the 80 to 95% optically pure product can be optically enriched to greater than 99.5% enantiomeric excess by controlled crystallization from ethyl acetate, isopropyl acetate, ethanol, methanol, or solvent mixtures of a hydrocarbon solvent such as hexanes, cyclohexane and esters such as ethyl acetate, isopropyl acetate or ethers such as methyl t-butyl ether.
  • the optically enriched product is crystallized from an ethyl acetate/hexane mixture in a 1:6 ratio v/v at -10°C to 20°C. This provides 99.5% ee pure Compound D .
  • this invention concerns a process of making compounds of formula D wherein:
  • aromatic solvents include, but are not limited to, benezene, toluene and xylene, preferably toluene.
  • Reducing agents include, but are not limited to metal hydrides such as sodium bis-methoxy, ethoxy aluminum hydride and diisobutylaluminum hydride preferably, diisobutylaluminium hydride.
  • metal hydrides such as sodium bis-methoxy, ethoxy aluminum hydride and diisobutylaluminum hydride preferably, diisobutylaluminium hydride.
  • the molar ratio of reducing agents to lactone should be approximately 1 to 1, or larger; preferably 1.25 to 1.
  • the reaction may be conducted from -80°C to -50°C, preferably -75°C to -60°C.
  • the reaction is allowed to proceed until substantially complete in about 1 to 2 hours, typically 1.25 or 1.5 hours.
  • the reaction can then be quenched by addition of C 1-6 alkan
  • reaction can be carried out at up to 100 atmospheres of pressure, the reaction is preferably carried at under ambient pressure;
  • tri-C 1-6 alkylchlorosilanes include but are not limited to tri-C 1-6 alkyl chlorosilane wherein each alkyl group is independently defined as C 1-6 alkyl. Preferred is tert-butyldimethylchlorosilane.
  • the second solvent includes, but is not limited to N,N-diC 1-6 alkyl carbonyl amide, such as N,N-dimethyl formamide (DMF) or toluene, tetrahydrofuron (THF), dichloromethane or other non-protic solvent; DMF is preferred.
  • Nitrogen containing bases include but are not limited to pyrrole, pyridene, pyrrolidine tri-C 1-3 alkyl amino such as triethyl amine and imidazole. Imidazole is preferred for complete reaction.
  • the molar ratio of base to Compound A' should be approximately 2 to 1 or greater. A ratio of 2.2 to 1 is typical.
  • the ratio of silane to Compound 2A' is approximately 1.1 to 1 up to 2.5 to 1; preferably 1 to 1.
  • the reaction should be allowed to proceed until complete in approximately 1 to 3 hours.
  • the reaction temperature may be 0 to 80°C., preferably 25 - 30°C.
  • reaction can be carried out at up to 100 atmospheres of pressure, the reaction is preferably carried out under ambient pressure.
  • the presence of oxygen is preferably minimized, such as by use of a nitrogen or other inert atmosphere.
  • hydroxyl groups may be protected with groups including trialkylsilyl, acetate, benzoate, and ether. See also Protective Groups in Organic Synthesis, Theodora W. Green, John Wiley and Sons (1981).
  • the third solvent includes but is not limited to etheral solvents such as diethyl ether di- n -butyl and diisopentyl ethers, anisole, cyclic ethers such as tetrahydropyran, 4-methyl-1,3-dioxane, tetrahydrofurfuryl methyl ether, ethyl ether, furan and tetrahydrofuran, or halocarbon solvents such as mono or di halo C 1-4 alkyl including methylene chloride. Methylene chloride is preferred.
  • the silyl bromide includes, but is not limited to tri C 1-6 alkylsilyl bromide with trimethylsilylbromide preferred for complete reaction.
  • the molar ratio of silyl bromide to compound B should be 1 to 1 or greater, preferably 1.1 - 1.3 to 1. The reaction is allowed to proceed until essentially complete in about 0.5 to 3 hours, typically 1.5 hours.
  • the reaction temperature is approximately -70 to -10°C, preferably -60°C.
  • reaction can be carried out at up to 100 atmospheres of pressure, the reaction is preferably carried at under ambient pressure.
  • the presence of oxygen is preferably minimized, such as by use of a nitrogen or other inert atmosphere.
  • the fourth solvent includes, but is not limited to ethers as broadly defined above; preferably THF.
  • the organo metallic reagent includes, but is not limited to those derived from aryl Grignard reagents such as 3,4,5-trimethoxy phenylmagnesium bromide in the presence of a copper salt such as copper cyanide or lithium tetrachlorocuprate.
  • the ratio of organometallic reagent to Compound 2C is approximately 1-1.5 to 1, preferably 1.4 to 1.
  • the reaction is allowed to proceed until essentially complete in about 0.5 to 3 hours. Typically 1.0 hours.
  • the reaction temperature is approximately -70 to -10°C, preferably -60°C.
  • reaction can be carried out at up to 100 atmospheres of pressure, the reaction is preferably carried at under ambient pressure.
  • the presence of oxygen is preferably minimized, such as by use of a nitrogen or other inert atmosphere.
  • PAF antagonists that can be produced from the compound of Formula 2D include (-)-(2S,5S)-2-(5(2-hydroxyethylsulfonyl)-4-(n-propoxy)-3-methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran; (-)-(2S,5S)-2-(5-(2-oxopropylsulfonyl)-4-(n-propoxy)-3-(3-phosphopropoxy)phenyl-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran; (-)-(2S,5S)-2-(5-(2-oxopropylsulfonyl)-4-(n-propoxy)3-(3-hydroxypropoxy)phenyl-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran; and (-)-(2S,5S)-2-(5-(2-hydroxyopropy
  • the starting materials are either known and available.
  • Step A 4[3-Methoxy-4-n-propyloxy-5-(2'-t-butyldimethylsiloxyethylsulfonyl)phenyl]-4-butyrolactol
  • Step B 5[3-Methoxy-4-n-propyloxy-5-(2'-t-butyldimethylsiloxyethylsulfonyl)phenyl]-1-(t-butyldimethylsiloxy)-butyrolactol
  • Step C Preparation of 1-tert-butyldimethylsiloxy-2-((2-methoxy-2-propyloxy-5-(tetrahydro-5-(3,4,5-trimethoxyphenyl)-2-furanyl)phenylsulfonyl-trans-(-)-ethane
  • the silyl ether B (0.829 Kg, 1.409 mole) was dissolved in CH 2 Cl 2 , under N 2 . The mixture was cooled to -60°C and then neat trimethylsilylbromide (0.232 L, 1.759 mole) was added. The mixture was stirred at -60°C for 1.5 hours. In a separate flask containing 3,4,5-trimethoxyphenylmagnesium bromide (0.9 M , 2.5L, 2.025 mole), at 0°C under N 2 was added the THF solution of Li 2 CuCl 4 (0.060 mL, 0.030 mole).
  • the mixture is cooled to ambient temperature and 40 mL of ethyl acetate is added.
  • the solution is stirred for 15 minutes and filtered through a celite pad.
  • the addition of ethyl acetate prior to filtration greatly improves phase separation.
  • the cake is washed with 25 ml of ethyl acetate.
  • the combined organic extracts are washed with 3 x 40 ml of an ammonium chloride:ammonium hydroxide solution, followed by 40 ml of water.
  • the ammonium chloride:ammonium hydroxide solution is prepared by adding approximately 65 ml of ammonium hydroxide solution (30%) to 300 ml of saturated aqueous ammonium chloride to a pH of 9.0. A pH range of 8.5-10.0 for this work has been determined to be satisfactory although pH 9.0 is favorable.
  • the organic extract is concentrated in vacuo to a volume of 4 ml.
  • the solution is flushed with 2 x 20 ml of acetonitrile and concentrated to ⁇ 4 mL.
  • the acetonitrile solution is used directly for the next step.
  • HPLC assay typically shows an 85-90% yield.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Furan Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Claims (5)

  1. Procédé de préparation de diisopinocamphéylchloroborane qui comprend :
    (a) la mise en contact du borane méthylsulfure dans un solvant éthéré avec le (1R)-(+)-α-pinène, pour former le diisopinocamphéylborane de formule 1
    Figure imgb0034
    (b) la mise en contact du produit de l'étape (a) avec un chlorure d'acide pour donner le diisopinocamphéylchloroborane de formule 2 :
    Figure imgb0035
     caractérisé en ce que le produit de l'étape (a) est utilisé dans l'étape (b) sans isolement ou purification distincte.
  2. Procédé selon la revendication 1, dans lequel le pinène possède une pureté optique d'un excès énantiomère d'environ 91 % à 95 %.
  3. Procédé selon la revendication 2, effectué à une température allant de - 25 à 25°C, jusqu'à ce qu'il soit pratiquement complet.
  4. Procédé selon la revendication 3, dans lequel le solvant éthéré est le tétrahydrofuranne.
  5. Procédé de réduction d'une cétone prochirale pour produire un alcool optiquement actif de pureté optique élevée qui comprend la réaction d'une cétone prochirale avec une composition réductrice de diisopinocamphéylchloroborane préparée conformément au procédé de la revendication 1, pendant de 7 heures à 24 jours à une température allant de - 25°C à la température ambiance et sous pression ambiante jusqu'à ce que la réaction soit complète.
EP91202396A 1990-09-24 1991-09-18 Préparation in-situ de diisopinocampheyl chloroborane Expired - Lifetime EP0478062B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US586933 1984-03-07
US58693390A 1990-09-24 1990-09-24

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EP0478062B1 true EP0478062B1 (fr) 1997-04-16

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EP (1) EP0478062B1 (fr)
JP (2) JP2546559B2 (fr)
CA (1) CA2050820A1 (fr)
DE (1) DE69125675T2 (fr)
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5545758A (en) * 1994-08-11 1996-08-13 Merck & Co., Inc. Process for the preparation of diisopinocampheylchloroborane
CA2453631A1 (fr) * 2001-07-17 2003-01-30 Pharmacia & Upjohn Company Procede et produits intermediaires utilises pour produire du latanoprost
US20060223999A1 (en) * 2006-05-10 2006-10-05 Chemagis Ltd. Process for preparing montelukast and precursors thereof
WO2014019166A1 (fr) * 2012-08-01 2014-02-06 上海威智医药科技有限公司 Procédé de production industrielle pour composé borane de haute activité
US9169183B1 (en) 2014-10-27 2015-10-27 Cpc Corporation, Taiwan Method for coproducing isobutene and ETBE from tert-Butanol mixture
CN113024588A (zh) * 2021-03-22 2021-06-25 成都诺和晟泰生物科技有限公司 一种手性N-Boc-吡咯烷-3-硼酸类化合物的制备方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
J.Org.Chem 1984,49,945-947 *

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JP2546559B2 (ja) 1996-10-23
CA2050820A1 (fr) 1992-03-25
JPH06345777A (ja) 1994-12-20
EP0478062A1 (fr) 1992-04-01
JP2667135B2 (ja) 1997-10-27
US5292946A (en) 1994-03-08
JPH0841074A (ja) 1996-02-13
LV12073A (lv) 1998-06-20
DE69125675T2 (de) 1997-11-20
LV12073B (en) 1998-09-20
DE69125675D1 (de) 1997-05-22

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